Pub Date : 2025-11-01Epub Date: 2025-08-21DOI: 10.1016/j.mvr.2025.104864
Jéssica Braga Amorim , Marina Dias Neto , Sandra Magalhães , António S. Barros
Peripheral artery disease (PAD) is a global health challenge, with current diagnostic methods, including the ankle-brachial index (ABI), having limitations, particularly in patients with arterial calcification. Near-infrared spectroscopy (NIRS) offers potential advantages as a non-invasive assessment tool, yet its clinical utility in PAD remains underexplored. This pilot study evaluated NIRS for differentiating between non-ischemic upper limbs and ischemic lower limbs, and assessed NIRS correlation with ABI. To do that, we performed an observational, cross-sectional study employing a convenience sample of 51 patients with PAD attending the vascular surgery outpatient clinic. A portable spectrometer recorded NIRS measurements from the right thumb and both halluces at rest. Random Forest classification was implemented to differentiate upper and lower limbs, revealing distinct NIRS patterns between upper and lower limbs, with an area under the ROC curve of 0.91 (95 % CI 0.88–0.94). Interval Partial Least Squares regression (iPLS) identified wavelength regions correlating with ABI, with the 1429–1463 nm interval being the most informative for ABI prediction, with a modest correlation (R2 = 0.167, RMSECV = 0.186).
NIRS demonstrated strong discriminative capability between non-ischemic upper and ischemic lower limbs in PAD. While the correlation between NIRS and ABI was modest, it suggests potential clinical relevance. These findings indicate that NIRS could be a rapid, portable, non-invasive complementary tool for PAD assessment.
外周动脉疾病（PAD）是一个全球性的健康挑战，目前的诊断方法，包括踝肱指数（ABI），具有局限性，特别是在动脉钙化患者中。近红外光谱（NIRS）作为一种非侵入性评估工具具有潜在的优势，但其在PAD中的临床应用仍未得到充分探索。本初步研究评估了NIRS用于区分非缺血上肢和缺血下肢，并评估了NIRS与ABI的相关性。为了做到这一点，我们进行了一项观察性横断面研究，采用51例在血管外科门诊就诊的PAD患者作为方便样本。一台便携式光谱仪记录了右拇指和两个幻觉在休息时的近红外光谱测量值。采用随机森林分类对上肢和下肢进行区分，上肢和下肢的NIRS模式明显，ROC曲线下面积为0.91 （95% CI 0.88-0.94）。区间偏最小二乘回归（iPLS）确定了与ABI相关的波长区域，其中1429-1463 nm区间对ABI预测的信息最丰富，相关性不大（R2 = 0.167, RMSECV = 0.186）。近红外光谱对非缺血性上肢和缺血性下肢有较强的区分能力。虽然NIRS和ABI之间的相关性不大，但它表明了潜在的临床相关性。这些发现表明，近红外光谱可能是一种快速、便携、无创的PAD评估补充工具。
{"title":"Pilot study on near-infrared spectroscopy in peripheral artery disease: Differentiating upper and lower limbs and its correlation with the ankle-brachial index","authors":"Jéssica Braga Amorim , Marina Dias Neto , Sandra Magalhães , António S. Barros","doi":"10.1016/j.mvr.2025.104864","DOIUrl":"10.1016/j.mvr.2025.104864","url":null,"abstract":"<div><div>Peripheral artery disease (PAD) is a global health challenge, with current diagnostic methods, including the ankle-brachial index (ABI), having limitations, particularly in patients with arterial calcification. Near-infrared spectroscopy (NIRS) offers potential advantages as a non-invasive assessment tool, yet its clinical utility in PAD remains underexplored. This pilot study evaluated NIRS for differentiating between non-ischemic upper limbs and ischemic lower limbs, and assessed NIRS correlation with ABI. To do that, we performed an observational, cross-sectional study employing a convenience sample of 51 patients with PAD attending the vascular surgery outpatient clinic. A portable spectrometer recorded NIRS measurements from the right thumb and both halluces at rest. Random Forest classification was implemented to differentiate upper and lower limbs, revealing distinct NIRS patterns between upper and lower limbs, with an area under the ROC curve of 0.91 (95 % CI 0.88–0.94). Interval Partial Least Squares regression (iPLS) identified wavelength regions correlating with ABI, with the 1429–1463 nm interval being the most informative for ABI prediction, with a modest correlation (R<sup>2</sup> = 0.167, RMSECV = 0.186).</div><div>NIRS demonstrated strong discriminative capability between non-ischemic upper and ischemic lower limbs in PAD. While the correlation between NIRS and ABI was modest, it suggests potential clinical relevance. These findings indicate that NIRS could be a rapid, portable, non-invasive complementary tool for PAD assessment.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104864"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shear stress enhances matrix metalloproteinase-2 (MMP-2) expression, which plays a critical role in bone marrow mesenchymal stem cells (BMSCs) migration and vascular remodeling via microenvironmental interactions with mouse aortic endothelial cells (MAECs). MAECs were exposed to disturbed flow using a custom flow device for 1, 3, or 5 h, and conditioned media (MAEC-CM) were collected. BMSCs migration in response to different MAEC-CM conditions was assessed by flow cytometry, transwell, and wound-healing assays. MMP-2 levels in MAEC-CM were modulated with recombinant protein or neutralizing antibody. LIMK1/Cofilin pathway activation was evaluated by western blot, and the LIMK1 inhibitor BMS-3 was used to confirm pathway function. Disturbed flow altered MAECs density, morphology, and intercellular gaps, with apoptosis increasing over time. ELISA showed MMP-2 secretion peaked at 3 h, coinciding with maximal BMSCs migration. Recombinant MMP-2 (400 ng/mL) further enhanced, while MMP-2 neutralizing antibody (100 ng/mL) suppressed, migration induced by MAEC-CM-3 h. Western blot revealed significant phosphorylation of LIMK1 and Cofilin after MAEC-CM-3 h treatment, with higher levels in recombinant MMP-2–treated groups compared to neutralization. BMS-3 significantly reduced MMP-2–induced BMSCs migration and phosphorylation of LIMK1/Cofilin without affecting total protein levels. These results indicate that shear stress–induced MMP-2 promotes BMSCs motility through LIMK1-dependent Cofilin activation. This study not only clarifies the molecular mechanism by which disturbed flow regulates BMSCs migration but also provides a theoretical basis for BMSC-mediated vascular repair, offering potential targets for future clinical applications.
{"title":"Shear stress-activated MMP-2 promotes BMSCs migration via the LIMK1/Cofilin axis during vascular remodeling","authors":"Yuan Liang , Jianjin Wu , Xingjian Fang , Yan Chang , Yumei Tang , Guangliang Diao , Cunping Yin","doi":"10.1016/j.mvr.2025.104863","DOIUrl":"10.1016/j.mvr.2025.104863","url":null,"abstract":"<div><div>Shear stress enhances matrix metalloproteinase-2 (MMP-2) expression, which plays a critical role in bone marrow mesenchymal stem cells (BMSCs) migration and vascular remodeling via microenvironmental interactions with mouse aortic endothelial cells (MAECs). MAECs were exposed to disturbed flow using a custom flow device for 1, 3, or 5 h, and conditioned media (MAEC-CM) were collected. BMSCs migration in response to different MAEC-CM conditions was assessed by flow cytometry, transwell, and wound-healing assays. MMP-2 levels in MAEC-CM were modulated with recombinant protein or neutralizing antibody. LIMK1/Cofilin pathway activation was evaluated by western blot, and the LIMK1 inhibitor BMS-3 was used to confirm pathway function. Disturbed flow altered MAECs density, morphology, and intercellular gaps, with apoptosis increasing over time. ELISA showed MMP-2 secretion peaked at 3 h, coinciding with maximal BMSCs migration. Recombinant MMP-2 (400 ng/mL) further enhanced, while MMP-2 neutralizing antibody (100 ng/mL) suppressed, migration induced by MAEC-CM-3 h. Western blot revealed significant phosphorylation of LIMK1 and Cofilin after MAEC-CM-3 h treatment, with higher levels in recombinant MMP-2–treated groups compared to neutralization. BMS-3 significantly reduced MMP-2–induced BMSCs migration and phosphorylation of LIMK1/Cofilin without affecting total protein levels. These results indicate that shear stress–induced MMP-2 promotes BMSCs motility through LIMK1-dependent Cofilin activation. This study not only clarifies the molecular mechanism by which disturbed flow regulates BMSCs migration but also provides a theoretical basis for BMSC-mediated vascular repair, offering potential targets for future clinical applications.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104863"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-21DOI: 10.1016/j.mvr.2025.104861
Mohamed J. Saadh , Omer Qutaiba B. Allela , Radhwan Abdul Kareem , Lalji Baldaniya , R. Roopashree , Vishal Thakur , Manpreet Kaur , Abdusamat Valiev , Hayder Naji Sameer , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil
Angiogenesis is critical for effective wound healing, supplying oxygen and nutrients to regenerating tissues. In chronic conditions like diabetes, impaired angiogenesis leads to delayed healing, chronic wounds, and significant healthcare burdens. Exosomes, nano-sized extracellular vesicles derived from cells such as mesenchymal stem cells (MSCs), amniotic epithelial cells, and keratinocytes, have emerged as key mediators in promoting angiogenesis. Laden with bioactive cargos—including microRNAs, proteins, and lipids—exosomes orchestrate endothelial cell proliferation, migration, and extracellular matrix remodeling to enhance vascularization. This review explores the molecular mechanisms by which exosomes drive angiogenesis, highlighting their role in modulating signaling pathways and immune responses critical for tissue repair. We evaluate the therapeutic promise of exosome-based delivery systems, integrating insights from biological, pharmaceutical, and cell-based approaches. By leveraging these advancements, exosomal therapies offer transformative potential for managing chronic wounds and ischemic conditions, paving the way for innovative regenerative medicine strategies.
{"title":"Harnessing exosomal mediators for advanced wound healing: Mechanisms and therapeutic potential in angiogenesis","authors":"Mohamed J. Saadh , Omer Qutaiba B. Allela , Radhwan Abdul Kareem , Lalji Baldaniya , R. Roopashree , Vishal Thakur , Manpreet Kaur , Abdusamat Valiev , Hayder Naji Sameer , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil","doi":"10.1016/j.mvr.2025.104861","DOIUrl":"10.1016/j.mvr.2025.104861","url":null,"abstract":"<div><div>Angiogenesis is critical for effective wound healing, supplying oxygen and nutrients to regenerating tissues. In chronic conditions like diabetes, impaired angiogenesis leads to delayed healing, chronic wounds, and significant healthcare burdens. Exosomes, nano-sized extracellular vesicles derived from cells such as mesenchymal stem cells (MSCs), amniotic epithelial cells, and keratinocytes, have emerged as key mediators in promoting angiogenesis. Laden with bioactive cargos—including microRNAs, proteins, and lipids—exosomes orchestrate endothelial cell proliferation, migration, and extracellular matrix remodeling to enhance vascularization. This review explores the molecular mechanisms by which exosomes drive angiogenesis, highlighting their role in modulating signaling pathways and immune responses critical for tissue repair. We evaluate the therapeutic promise of exosome-based delivery systems, integrating insights from biological, pharmaceutical, and cell-based approaches. By leveraging these advancements, exosomal therapies offer transformative potential for managing chronic wounds and ischemic conditions, paving the way for innovative regenerative medicine strategies.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104861"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To investigate the hypothesis that the wall-to-lumen ratio (WLR) of retinal arteries is predictive of morbidity and mortality in patients with end-stage chronic kidney disease (CKD).
Methods
Prospective single center clinical study. In 83 patients with CKD (average age (±SD) 75.8 (±11.4) years), arterial metrics in the retinal vasculature were measured using adaptive optics ophthalmoscopy (AOO; rtx1, ImagineEyes, France). Multivariate analysis including vascular metrics and biological parameters was done to identify predictive risk factors of the morbidity and mortality rates at 3 years.
Results
At inclusion, the mean (±SD) wall-to-lumen ratio (WLR) was 0,34 (± 0,17). No correlation was found between blood pressure and the WLR. The 1, 2 and 3-year survival rates were 74.7 %, 57.3 % and 42.1 %, respectively. The 1, 2 and 3-year rates of nonfatal cardiovascular events were 25.3 %, 42.7 % and 56.5 %, respectively. Four patients were lost to follow-up. Based on a Cox model, the cumulative 3-year relative risk of death or cardiovascular event was inversely correlated to the initial WLR (RR 2.5 if WLR <0.36, 2.1 if <0.3, 4.9 if <0.27), age over 80 years (RR 1.9), and sedentarity (RR 2.3). Metabolic factors were not predictive of event-free survival.
Conclusions
In patients with end-stage CKD, a lower WLR is associated with a higher morbidity and mortality rate at 3 years. Retinal vascular metrics may therefore provide novel biomarkers for the prediction of event-free survival in CKD. Additional studies are necessary to elucidate the underlying relationship.
{"title":"Prognostic value of the wall-to-lumen ratio of retinal arteries in patients with end-stage chronic kidney disease","authors":"Céline Faure , Cindy Castrale , Anaïs Benabed , Romain Lezé , Pauline Cognard , Michel Paques","doi":"10.1016/j.mvr.2025.104860","DOIUrl":"10.1016/j.mvr.2025.104860","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the hypothesis that the wall-to-lumen ratio (WLR) of retinal arteries is predictive of morbidity and mortality in patients with end-stage chronic kidney disease (CKD).</div></div><div><h3>Methods</h3><div>Prospective single center clinical study. In 83 patients with CKD (average age (±SD) 75.8 (±11.4) years), arterial metrics in the retinal vasculature were measured using adaptive optics ophthalmoscopy (AOO; rtx1, ImagineEyes, France). Multivariate analysis including vascular metrics and biological parameters was done to identify predictive risk factors of the morbidity and mortality rates at 3 years.</div></div><div><h3>Results</h3><div>At inclusion, the mean (±SD) wall-to-lumen ratio (WLR) was 0,34 (± 0,17). No correlation was found between blood pressure and the WLR. The 1, 2 and 3-year survival rates were 74.7 %, 57.3 % and 42.1 %, respectively. The 1, 2 and 3-year rates of nonfatal cardiovascular events were 25.3 %, 42.7 % and 56.5 %, respectively. Four patients were lost to follow-up. Based on a Cox model, the cumulative 3-year relative risk of death or cardiovascular event was inversely correlated to the initial WLR (RR 2.5 if WLR <0.36, 2.1 if <0.3, 4.9 if <0.27), age over 80 years (RR 1.9), and sedentarity (RR 2.3). Metabolic factors were not predictive of event-free survival.</div></div><div><h3>Conclusions</h3><div>In patients with end-stage CKD, a lower WLR is associated with a higher morbidity and mortality rate at 3 years. Retinal vascular metrics may therefore provide novel biomarkers for the prediction of event-free survival in CKD. Additional studies are necessary to elucidate the underlying relationship.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104860"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-20DOI: 10.1016/j.mvr.2025.104859
Maya Salame, Marianne Fenech
The formation of the cell-free layer (CFL) near vessel walls plays a critical role in microcirculatory function, influencing blood rheology, oxygen delivery, and endothelial interactions. While hematocrit (Ht) is a well-established determinant of CFL thickness, the influence of shear-related parameters remains debated due to conflicting findings in the literature. In this study, we systematically quantified the optical CFL thickness () in circular glass microchannels (25–50 μm diameter) under varying hematocrit levels (5–20 %), flow rates, and suspension media (phosphate-buffered saline and plasma). High-resolution microfluidic imaging and micro-particle image velocimetry (μPIV) were used to extract local velocity fields and calculate shear rate gradients (∇).
Rather than treating ∇ as an imposed variable, we characterize it as a flow-derived descriptor of the local hydrodynamic environment. Across conditions, ∇ showed stronger correlations with CFL thickness than bulk shear rate. In PBS, increasing ∇ was associated with reduced CFL thickness, likely due to enhanced shear-induced dispersion. In contrast, in plasma, higher ∇ values promoted disaggregation of red blood cell (RBC) aggregates and restored hydrodynamic lift, resulting in thicker CFLs. These trends underscore the importance of considering both the suspension medium and spatial shear variations when interpreting RBC behavior.
Comparison with prior in vitro, in vivo, and computational studies suggests that discrepancies in reported CFL trends can often be reconciled by accounting for differences in aggregation potential and local shear rate gradients. This work provides a unified experimental framework for interpreting CFL dynamics and highlights ∇ as a valuable parameter for describing flow-mediated RBC redistribution in the microcirculation.
{"title":"Key contributors to cell-free layer formation: An experimental investigation of hematocrit and shear rate gradient","authors":"Maya Salame, Marianne Fenech","doi":"10.1016/j.mvr.2025.104859","DOIUrl":"10.1016/j.mvr.2025.104859","url":null,"abstract":"<div><div>The formation of the cell-free layer (CFL) near vessel walls plays a critical role in microcirculatory function, influencing blood rheology, oxygen delivery, and endothelial interactions. While hematocrit (Ht) is a well-established determinant of CFL thickness, the influence of shear-related parameters remains debated due to conflicting findings in the literature. In this study, we systematically quantified the optical CFL thickness (<span><math><msub><mi>δ</mi><mi>o</mi></msub></math></span>) in circular glass microchannels (25–50 μm diameter) under varying hematocrit levels (5–20 %), flow rates, and suspension media (phosphate-buffered saline and plasma). High-resolution microfluidic imaging and micro-particle image velocimetry (μPIV) were used to extract local velocity fields and calculate shear rate gradients (∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span>).</div><div>Rather than treating ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> as an imposed variable, we characterize it as a flow-derived descriptor of the local hydrodynamic environment. Across conditions, ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> showed stronger correlations with CFL thickness than bulk shear rate. In PBS, increasing ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> was associated with reduced CFL thickness, likely due to enhanced shear-induced dispersion. In contrast, in plasma, higher ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> values promoted disaggregation of red blood cell (RBC) aggregates and restored hydrodynamic lift, resulting in thicker CFLs. These trends underscore the importance of considering both the suspension medium and spatial shear variations when interpreting RBC behavior.</div><div>Comparison with prior in vitro, in vivo, and computational studies suggests that discrepancies in reported CFL trends can often be reconciled by accounting for differences in aggregation potential and local shear rate gradients. This work provides a unified experimental framework for interpreting CFL dynamics and highlights ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> as a valuable parameter for describing flow-mediated RBC redistribution in the microcirculation.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104859"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-30DOI: 10.1016/j.mvr.2025.104855
Nien-Wen Hu , M.M.N. Hossain , Julia Withrow , Ryan Walker , Ali Kazempour , Nikolaos Tsoukias , Donald G. Welsh , Walter L. Murfee , Peter Balogh
The objective of this study was to computationally estimate the effects of vessel specific vasoconstriction on immediate shear stress changes across microvascular networks. Shear stress due to microvascular blood flow is an established initiator of ion-mediated signaling along microvessels which regulates control of microcirculatory blood flow. Yet, beyond initiating local vasomotion in a vessel, shear stress as a vasoconduction signal itself and characteristics of hydrodynamic propagation via blood flow are not well understood. In the current work, we use images of mesenteric microvascular networks from adult rat tissues and a network segmental blood flow model to simulate various vessel constriction scenarios and estimate subsequent shear stress changes and distances these changes spread from the site of constriction. Scenarios involving both arteriolar constriction and capillary constriction are considered, in addition to a microvascular network from muscle tissue. The findings generally reveal heterogenous and physiologically relevant shear stress changes across the networks for all cases, with magnitudes spanning a wide range and can exceed 30 dyne/cm2. Further, physiological relevant wall shear changes were predicted at distances several mm from the stimulus site. Spatial patterns of shear stress change relative to network topology and capillary density are also identified. Altogether, the results invigorate consideration and discussion about shear stress as a potential player in vasoconduction responses.
{"title":"Identification of shear stress as a potential vasoconduction signal across microvascular networks","authors":"Nien-Wen Hu , M.M.N. Hossain , Julia Withrow , Ryan Walker , Ali Kazempour , Nikolaos Tsoukias , Donald G. Welsh , Walter L. Murfee , Peter Balogh","doi":"10.1016/j.mvr.2025.104855","DOIUrl":"10.1016/j.mvr.2025.104855","url":null,"abstract":"<div><div>The objective of this study was to computationally estimate the effects of vessel specific vasoconstriction on immediate shear stress changes across microvascular networks. Shear stress due to microvascular blood flow is an established initiator of ion-mediated signaling along microvessels which regulates control of microcirculatory blood flow. Yet, beyond initiating local vasomotion in a vessel, shear stress as a vasoconduction signal itself and characteristics of hydrodynamic propagation via blood flow are not well understood. In the current work, we use images of mesenteric microvascular networks from adult rat tissues and a network segmental blood flow model to simulate various vessel constriction scenarios and estimate subsequent shear stress changes and distances these changes spread from the site of constriction. Scenarios involving both arteriolar constriction and capillary constriction are considered, in addition to a microvascular network from muscle tissue. The findings generally reveal heterogenous and physiologically relevant shear stress changes across the networks for all cases, with magnitudes spanning a wide range and can exceed 30 dyne/cm<sup>2</sup>. Further, physiological relevant wall shear changes were predicted at distances several mm from the stimulus site. Spatial patterns of shear stress change relative to network topology and capillary density are also identified. Altogether, the results invigorate consideration and discussion about shear stress as a potential player in vasoconduction responses.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104855"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-08DOI: 10.1016/j.mvr.2025.104857
Chunli Yang , Huijuan Zhao , Xiaomin Wu , Wei Tuo , Ling Hou , Dahai Chai , Guanghua Li
This study examined the autophagy and apoptosis of vascular endothelial cells in spontaneously hypertensive rats (SHRs) under intermittent heat stress and determined whether the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51 like autophagy activating kinase (ULK1) pathway is involved in autophagy regulation. Wistar-Kyoto (WKY) rats were assigned to control (WKY-CN), intermittent heat stress (WKY-8), and continuous heat stress (WKY-24) groups. SHRs were also assigned to three groups: SHR-CN, SHR-8, and SHR-24. Western blotting assay, immunohistochemical assay, and immunofluorescence assay were performed for observing expression of proteins related to autophagy and apoptosis and the AMPK/mTOR/ULK1 pathway. Vascular endothelial cells underwent autophagy and apoptosis following heat stress, as revealed by high expression of autophagy- and apoptosis-related proteins. Heat stress elevated AMPK and ULK1 expression levels, whereas it decreased mTOR phosphorylation in SHR-8 and SHR-24 groups. Finally, the rats in SHR-8 group were administered an autophagy inducer (rapamycin, Rapa) and inhibitor (3-Methyladenine, 3-MA), respectively, for evaluating autophagy induction and inhibition. Following Rapa administration, LC3-II/LC3-I and Caspase-3 expression levels were elevated in the intermittent heat stress groups as compared to those in the control groups; in contrast, 3-MA attenuated cell death in the intermittent heat stress groups. Overall, this study demonstrated that intermittent heat stress elicits autophagy and apoptosis processes in vascular endothelial cells and that the AMPK/mTOR/ULK1 pathway participates in regulating autophagy and apoptosis.
{"title":"Intermittent heat stress facilitates the autophagy and apoptosis of the vascular endothelium in spontaneously hypertensive rats via the AMPK/mTOR/ULK1 pathway","authors":"Chunli Yang , Huijuan Zhao , Xiaomin Wu , Wei Tuo , Ling Hou , Dahai Chai , Guanghua Li","doi":"10.1016/j.mvr.2025.104857","DOIUrl":"10.1016/j.mvr.2025.104857","url":null,"abstract":"<div><div>This study examined the autophagy and apoptosis of vascular endothelial cells in spontaneously hypertensive rats (SHRs) under intermittent heat stress and determined whether the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51 like autophagy activating kinase (ULK1) pathway is involved in autophagy regulation. Wistar-Kyoto (WKY) rats were assigned to control (WKY-CN), intermittent heat stress (WKY-8), and continuous heat stress (WKY-24) groups. SHRs were also assigned to three groups: SHR-CN, SHR-8, and SHR-24. Western blotting assay, immunohistochemical assay, and immunofluorescence assay were performed for observing expression of proteins related to autophagy and apoptosis and the AMPK/mTOR/ULK1 pathway. Vascular endothelial cells underwent autophagy and apoptosis following heat stress, as revealed by high expression of autophagy- and apoptosis-related proteins. Heat stress elevated AMPK and ULK1 expression levels, whereas it decreased mTOR phosphorylation in SHR-8 and SHR-24 groups. Finally, the rats in SHR-8 group were administered an autophagy inducer (rapamycin, Rapa) and inhibitor (3-Methyladenine, 3-MA), respectively, for evaluating autophagy induction and inhibition. Following Rapa administration, LC3-II/LC3-I and Caspase-3 expression levels were elevated in the intermittent heat stress groups as compared to those in the control groups; in contrast, 3-MA attenuated cell death in the intermittent heat stress groups. Overall, this study demonstrated that intermittent heat stress elicits autophagy and apoptosis processes in vascular endothelial cells and that the AMPK/mTOR/ULK1 pathway participates in regulating autophagy and apoptosis.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104857"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.mvr.2025.104842
Chihiro Matsui , Reiko Tsukuura , Toko Miyazaki , Shigeki Ishibashi , Takakuni Tanaka , Takayoshi Nishimura , Go Arai , Joseph M. Escandón , Hatan Mortada , Takumi Yamamoto
Introduction
Lymphedema is a chronic, progressive disorder characterized by impaired lymphatic transport, tissue swelling, and fibrosis. This study used video-capillaroscopy, a high-resolution imaging technique, to assess superficial collecting lymphatic vessels and their vasa vasorum in patients with lymphedema. By comparing these microvascular structures to those in healthy tissue, we aimed to identify early vascular changes contributing to disease progression.
Methods
VC recordings were retrospectively analyzed from 28 limbs in 17 patients with lower extremity lymphedema and 53 lymphatic vessels in 12 cancer patients undergoing reconstructive surgery. In the latter group, observations were performed on normal subcutaneous tissue exposed at the donor site during flap harvest. These areas showed no tumor involvement, regional metastasis, or prior chemotherapy/radiotherapy. Thus, all normal tissue observations were made on untreated, unaffected sites. VCLs were classified into six stages (0–5) based on morphology and flow. Vessel diameter and red blood cell (RBC) velocity were measured. Statistical significance was set at p < 0.05.
Results
In normal donor tissue, mean VCL main vessel diameter and RBC velocity were 0.038 ± 0.031 mm and 185 ± 160.5 μm/s. In lymphedema, these values were reduced to 0.033 ± 0.024 mm and 28.3 ± 36.8 μm/s (p < 0.001). VCL Stage 0 showed preserved flow (p = 0.178), while Stages 1–5 exhibited progressive impairment.
Conclusion
These findings suggest that early ischemic changes in the vasa vasorum may precede lymphatic dysfunction and fibrosis in lymphedema. Preserving microvascular integrity should be a therapeutic focus, alongside drainage support. Further studies are needed to clarify clinical relevance and optimize treatment strategies.
{"title":"Comparative analysis of superficial collecting lymph vessels in normal tissue and lymphedema using video-capillaroscopy","authors":"Chihiro Matsui , Reiko Tsukuura , Toko Miyazaki , Shigeki Ishibashi , Takakuni Tanaka , Takayoshi Nishimura , Go Arai , Joseph M. Escandón , Hatan Mortada , Takumi Yamamoto","doi":"10.1016/j.mvr.2025.104842","DOIUrl":"10.1016/j.mvr.2025.104842","url":null,"abstract":"<div><h3>Introduction</h3><div>Lymphedema is a chronic, progressive disorder characterized by impaired lymphatic transport, tissue swelling, and fibrosis. This study used video-capillaroscopy, a high-resolution imaging technique, to assess superficial collecting lymphatic vessels and their vasa vasorum in patients with lymphedema. By comparing these microvascular structures to those in healthy tissue, we aimed to identify early vascular changes contributing to disease progression.</div></div><div><h3>Methods</h3><div>VC recordings were retrospectively analyzed from 28 limbs in 17 patients with lower extremity lymphedema and 53 lymphatic vessels in 12 cancer patients undergoing reconstructive surgery. In the latter group, observations were performed on normal subcutaneous tissue exposed at the donor site during flap harvest. These areas showed no tumor involvement, regional metastasis, or prior chemotherapy/radiotherapy. Thus, all normal tissue observations were made on untreated, unaffected sites. VCLs were classified into six stages (0–5) based on morphology and flow. Vessel diameter and red blood cell (RBC) velocity were measured. Statistical significance was set at <em>p</em> < 0.05.</div></div><div><h3>Results</h3><div>In normal donor tissue, mean VCL main vessel diameter and RBC velocity were 0.038 ± 0.031 mm and 185 ± 160.5 μm/s. In lymphedema, these values were reduced to 0.033 ± 0.024 mm and 28.3 ± 36.8 μm/s (<em>p</em> < 0.001). VCL Stage 0 showed preserved flow (<em>p</em> = 0.178), while Stages 1–5 exhibited progressive impairment.</div></div><div><h3>Conclusion</h3><div>These findings suggest that early ischemic changes in the vasa vasorum may precede lymphatic dysfunction and fibrosis in lymphedema. Preserving microvascular integrity should be a therapeutic focus, alongside drainage support. Further studies are needed to clarify clinical relevance and optimize treatment strategies.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104842"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.mvr.2025.104846
Aurelia Bucciarelli, Dominik Obrist
Efficient oxygen delivery in the brain relies on a finely tuned balance between vascular architecture and dynamic flow regulation. While red blood cells (RBCs) passively flow through the capillary network, neurovascular coupling ensures that the blood supply adapts to meet the metabolic demands of active neurons. Pericytes, contractile cells embedded in the capillary walls, play a key role in this process by modulating capillary diameter in response to neural signals. While pericytes are believed to enable rapid and localized blood flow regulation, their contributions in time and space remain debated. This study investigates the effects of pericyte-like vessel dilation (i.e., pericyte relaxation) on RBC distribution and flow dynamics using an in vitro microfluidic model. We investigate how pericyte-induced dynamic cross-sectional changes affect RBC distribution and velocity in a capillary network. By employing a programmable pressure pump to simulate gradual variations in capillary diameter, we observed that short-time dilation increased RBC velocity and hematocrit near the dilation site, enhancing localized perfusion. In contrast, prolonged dilation led to a network-wide RBC redistribution minimizing hydraulic resistance, ultimately depleting hematocrit due to the network Fåhræus effect. These findings highlight the dynamic and adaptive nature of capillary blood flow, where sustained localized changes can propagate into systemic effects over time. More broadly, this study provides new insights into the interplay between localized flow regulation and systemic capillary network dynamics, revealing how geometric and dynamic factors govern RBC behavior and perfusion.
{"title":"Influence of pericyte-like vessel dilation on RBC flux in an In Vitro microvascular network","authors":"Aurelia Bucciarelli, Dominik Obrist","doi":"10.1016/j.mvr.2025.104846","DOIUrl":"10.1016/j.mvr.2025.104846","url":null,"abstract":"<div><div>Efficient oxygen delivery in the brain relies on a finely tuned balance between vascular architecture and dynamic flow regulation. While red blood cells (RBCs) passively flow through the capillary network, neurovascular coupling ensures that the blood supply adapts to meet the metabolic demands of active neurons. Pericytes, contractile cells embedded in the capillary walls, play a key role in this process by modulating capillary diameter in response to neural signals. While pericytes are believed to enable rapid and localized blood flow regulation, their contributions in time and space remain debated. This study investigates the effects of pericyte-like vessel dilation (i.e., pericyte relaxation) on RBC distribution and flow dynamics using an <em>in vitro</em> microfluidic model. We investigate how pericyte-induced dynamic cross-sectional changes affect RBC distribution and velocity in a capillary network. By employing a programmable pressure pump to simulate gradual variations in capillary diameter, we observed that short-time dilation increased RBC velocity and hematocrit near the dilation site, enhancing localized perfusion. In contrast, prolonged dilation led to a network-wide RBC redistribution minimizing hydraulic resistance, ultimately depleting hematocrit due to the network Fåhræus effect. These findings highlight the dynamic and adaptive nature of capillary blood flow, where sustained localized changes can propagate into systemic effects over time. More broadly, this study provides new insights into the interplay between localized flow regulation and systemic capillary network dynamics, revealing how geometric and dynamic factors govern RBC behavior and perfusion.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104846"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-06DOI: 10.1016/j.mvr.2025.104856
Hugang Jiang, Rui Wang, Ai Liu, Jiakun Liu, Xiaying Wang, Wenyan Lin, Chunzhen Ren, Kai Liu, Xinke Zhao, Yingdong Li
Background: Coronary microvascular dysfunction (CMVD) significantly impairs cardiac function and worsens prognosis in patients with cardiovascular diseases, yet no definitively effective pharmacological treatment currently exists. Endothelial cell injury stands as the core pathogenic mechanism of CMVD, however, the molecular mechanisms underlying X-ray radiation-induced endothelial damage remain poorly understood. Although our research group has previously demonstrated that RAS-RH possesses pro-angiogenic properties, its therapeutic potential and mechanistic basis in treating CMVD remain unexplored. Aim This study aims to investigate the potential mechanism by which RAS-RH mitigates radiation-induced coronary microcirculation dysfunction through the inhibition of mitochondrial membrane permeability transition pore (mPTP) opening in endothelial cells.
Methods: We employed a comprehensive set of techniques, including transthoracic echocardiography, coronary microvessel casting technique, carstairs and heidenhain staining, immunohistochemistry, enzyme-linked immunosorbent assay, Western blot, fluorescence in situ hybridization, transmission electron microscopy, TUNEL assay, and flow cytometry, to systematically evaluate cardiac function, coronary vascular structure, myocardial pathological changes, ultrastructural damage, apoptosis, and protein marker expression in an animal model.
Results: In the CMVD rat model, X-ray radiation induced cardiac dysfunction, accompanied by elevated levels of vasoactive substances (TXA₂, ET-1, and vWF) and reduced nitric oxide (NO) production. Coronary vascular injury worsened, evidenced by decreased vascular volume, narrowed lumen diameter, and shortened vessel length. Additionally, capillary density was reduced, myocardial ischemia was exacerbated, and intravascular thrombosis was aggravated. At the molecular level, mPTP-related proteins (CypD, VDAC, F₁F₀-ATPase and ANT) exhibited abnormal expression, while apoptosis-related proteins (Cytc, AIF, caspase-9, and caspase-3) were upregulated, leading to increased apoptotic severity. Ultrastructural damage in cardiomyocytes and telocytes was aggravated, and miR-126 expression was downregulated. These findings suggest that X-ray radiation induces CMVD by triggering excessive mPTP opening in endothelial cells. Notably, interventions with RAS-RH, miR-126 agomir and RAS-RH + miR-126 agomir significantly ameliorated these pathological changes to varying degrees. This demonstrates that RAS-RH mitigates X-ray radiation-induced CMVD by upregulating miR-126 to suppress mPTP overactivation.
Conclusion: RAS-RH effectively ameliorates X-ray radiation-induced CMVD by modulating miR-126 expression to inhibit pathological opening of the mPTP in endothelial cells. This finding provides novel mechanistic evidence supporting RAS-RH as a therapeutic strategy for CMVD.
{"title":"RAS-RH up-regulates the level of miR-126 and inhibits the opening of mPTP in a rat model of coronary microvascular disease.","authors":"Hugang Jiang, Rui Wang, Ai Liu, Jiakun Liu, Xiaying Wang, Wenyan Lin, Chunzhen Ren, Kai Liu, Xinke Zhao, Yingdong Li","doi":"10.1016/j.mvr.2025.104856","DOIUrl":"10.1016/j.mvr.2025.104856","url":null,"abstract":"<p><strong>Background: </strong>Coronary microvascular dysfunction (CMVD) significantly impairs cardiac function and worsens prognosis in patients with cardiovascular diseases, yet no definitively effective pharmacological treatment currently exists. Endothelial cell injury stands as the core pathogenic mechanism of CMVD, however, the molecular mechanisms underlying X-ray radiation-induced endothelial damage remain poorly understood. Although our research group has previously demonstrated that RAS-RH possesses pro-angiogenic properties, its therapeutic potential and mechanistic basis in treating CMVD remain unexplored. Aim This study aims to investigate the potential mechanism by which RAS-RH mitigates radiation-induced coronary microcirculation dysfunction through the inhibition of mitochondrial membrane permeability transition pore (mPTP) opening in endothelial cells.</p><p><strong>Methods: </strong>We employed a comprehensive set of techniques, including transthoracic echocardiography, coronary microvessel casting technique, carstairs and heidenhain staining, immunohistochemistry, enzyme-linked immunosorbent assay, Western blot, fluorescence in situ hybridization, transmission electron microscopy, TUNEL assay, and flow cytometry, to systematically evaluate cardiac function, coronary vascular structure, myocardial pathological changes, ultrastructural damage, apoptosis, and protein marker expression in an animal model.</p><p><strong>Results: </strong>In the CMVD rat model, X-ray radiation induced cardiac dysfunction, accompanied by elevated levels of vasoactive substances (TXA₂, ET-1, and vWF) and reduced nitric oxide (NO) production. Coronary vascular injury worsened, evidenced by decreased vascular volume, narrowed lumen diameter, and shortened vessel length. Additionally, capillary density was reduced, myocardial ischemia was exacerbated, and intravascular thrombosis was aggravated. At the molecular level, mPTP-related proteins (CypD, VDAC, F₁F₀-ATPase and ANT) exhibited abnormal expression, while apoptosis-related proteins (Cytc, AIF, caspase-9, and caspase-3) were upregulated, leading to increased apoptotic severity. Ultrastructural damage in cardiomyocytes and telocytes was aggravated, and miR-126 expression was downregulated. These findings suggest that X-ray radiation induces CMVD by triggering excessive mPTP opening in endothelial cells. Notably, interventions with RAS-RH, miR-126 agomir and RAS-RH + miR-126 agomir significantly ameliorated these pathological changes to varying degrees. This demonstrates that RAS-RH mitigates X-ray radiation-induced CMVD by upregulating miR-126 to suppress mPTP overactivation.</p><p><strong>Conclusion: </strong>RAS-RH effectively ameliorates X-ray radiation-induced CMVD by modulating miR-126 expression to inhibit pathological opening of the mPTP in endothelial cells. This finding provides novel mechanistic evidence supporting RAS-RH as a therapeutic strategy for CMVD.</p>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":" ","pages":"104856"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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